The present invention relates in general to reducing brain damage resulting from seizures and in particular to reducing brain damage resulting from seizures caused by nerve agents.
One aspect of chemical warfare involves exposing the enemy to nerve agents. The best defense to nerve agent exposure is, of course, to prevent the soldier from being exposed to the nerve agent. However, exposure to nerve agents may occur and must be treated. Certain nerve agents cause seizures. Examples of organophosphorus nerve agents that cause seizures are GB (sarin), GD (soman), GA (tabun) and GF. It cannot be certain that every victim on the chemical battlefield will receive the fielded therapy regimen (atropine, 2-PAM, diazepam) within the prescribed window of opportunity. These victims may experience prolonged seizure episodes lasting one or more hours. Availability of a drug that will stop development of the lesions after prolonged seizure epilectus would be a valuable adjunct to the current therapeutic regimens.
Throughout the specification, certain publications are identified parenthetically by author and date. A complete identification of these publications is given at the end of the specification. The publication entitled "Neuroprotective Effects of HU-211 on Brain Damage Resulting from Soman-induced Seizures" by Filbert, M. G.; Forster, J. S.; Smith, C. D.; Ballough, G. P.; Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, Oct. 1998, is hereby expressly incorporated by reference. Exposure to high concentrations of the nerve agent soman (pinacolylymethylphosphonofluoridate), an organophosphorus (OP) inhibitor of cholinesterases, leads to the development of seizures (Taylor, 1985) and brain damage (Shih and McDonough, 1997; Ballough el al. 1998). Seizure-related brain damage (SRBD) resulting from exposure to soman is considered to be excitotoxic (Olney et al., 1983). Soman-induced seizures are initiated by the high levels of acetylcholine that accumulate as a result of the irreversible inhibition of acetylcholinesterase (AChE). As the duration of seizures increases, excitatory amino acids released by elevated levels of acetylcholine assume control over the seizures and are maintained by this neurotransmitter system (Shih and McDonough, 1997; Olney et al., 1983; Sparenborg et al., 1992). This conclusion is supported by studies demonstrating that soman-induced seizures and the resulting brain damage can be ameliorated by administration of antagonists of N-methyl-D-aspartate (NMDA) such as MK-801 (Braitman and Sparenborg, 1989; Clifford et al., 1989, 1990). Because MK-801 produces neurotoxic effects (Fix et al., 1993), it is not likely to be useful clinically. Therefore, a need exists for a clinically useful neuroprotectant to reduce brain damage caused by organophosphorus nerve agent-induced seizures.
HU-211 (dexanabinol, (+)-(3S,4S)-7-hydroxy-.DELTA.-6 tetrahydro cannabinol 1,1 dimethylheptyl) is a nonpsychotropic cannabinoid that has been shown to have neuroprotectant effects in neurons exposed to excitotoxins in culture (Eshhar et al., 1993, 1995). HU-211 antagonizes glutamatergic neurotransmission in the brain and also inhibits metabolic events that lead to neuronal degeneration (Biegon and Bar Joseph, 1995; Shohami et al., 1997). In addition to having NMDA-blocking activity, HU-211 appears to act as a potent scavenger of peroxy and hydroxy radicals (Shohami et al., 1997) and to reduce the destabilization of calcium homeostasis (Nadler et al., 1995; Striem et al., 1996). HU-211 has been evaluated as a neuroprotectant in animal models of closed head injury, optic nerve crush, and global or focal ischemia. In these models, a single injection of HU-211 given after the insult conferred significant increases in neuronal survival. It is currently being evaluated in phase 1 clinical trials (Biegon, 1998, personal communication). The present invention is a new use for HU-211. The new use is to reduce brain damage resulting from seizures caused by organophosphorus nerve agents.